Every drug substance and drug product contains small amounts of substances other than the active ingredient. These are called pharmaceutical impurities. Even at very low levels, some impurities can affect the safety, efficacy or stability of a medicine, which is why regulators expect every manufacturer to identify, measure and control them.
This guide explains what pharmaceutical impurities are, the main types, where they come from, how they are controlled and how impurity reference standards make that control possible.
What is a pharmaceutical impurity?
A pharmaceutical impurity is any component of a drug substance (API) or drug product that is not the intended chemical entity or an excipient. Impurities can enter at any stage, from raw materials and synthesis to formulation, packaging and storage.
Impurities matter for three reasons:
- Safety: some impurities are toxic, and a few (such as nitrosamines) are potential carcinogens even at trace levels.
- Efficacy: high impurity levels can mean less active ingredient and lower potency.
- Stability: rising degradation products signal that a product is breaking down and may not last its shelf life.
Types of pharmaceutical impurities
The ICH Q3A and Q3B guidelines group impurities into three broad classes.
1. Organic impurities
These are the most common and the most closely watched. They include:
- Starting materials and intermediates that did not react completely.
- By-products formed by side reactions during synthesis.
- Degradation products formed when the API breaks down.
- Reagents, ligands and catalysts used in the process.
- Isomers: including enantiomers and positional isomers of the API.
2. Inorganic impurities
These include reagents, inorganic salts, heavy metals and elemental impurities (for example residues of palladium or other metal catalysts), filter aids and charcoal. Elemental impurities are covered separately by ICH Q3D.
3. Residual solvents
Organic solvents used in synthesis or purification that are not completely removed. ICH Q3C classifies them by toxicity (Class 1, 2 and 3) and sets permitted daily exposure limits.
Special case (mutagenic impurities): impurities that can damage DNA, such as nitrosamines, are controlled under ICH M7 at much lower levels than ordinary impurities. Read our guide to nitrosamine impurities.
Process-related impurities vs degradation products
From a practical point of view, organic impurities fall into two families that need different control strategies.
| Process-related impurities | Degradation products | |
|---|---|---|
| Where they come from | Synthesis and purification: starting materials, intermediates, by-products, reagents | Breakdown of the API during manufacture, storage or in the formulation |
| Main triggers | Route of synthesis, reaction conditions, raw-material quality | Heat, moisture, light, oxygen, pH, interaction with excipients or packaging |
| How they are controlled | Process optimisation, purification, specifications on raw materials and intermediates | Formulation design, packaging, storage conditions, stability testing |
| When they are studied | Process development and validation | Forced degradation and stability studies |
A degradation product found in stability samples will often not appear in the freshly made API, which is why both forced degradation studies and long-term stability testing are needed.
How impurity limits are set: ICH Q3A thresholds
ICH Q3A defines three thresholds for impurities in new drug substances, based on the maximum daily dose:
| Maximum daily dose | Reporting threshold | Identification threshold | Qualification threshold |
|---|---|---|---|
| ≤ 2 g/day | 0.05% | 0.10% or 1.0 mg/day (whichever is lower) | 0.15% or 1.0 mg/day (whichever is lower) |
| > 2 g/day | 0.03% | 0.05% | 0.05% |
- Reporting threshold: above this level an impurity must be reported.
- Identification threshold: above this level its structure must be identified.
- Qualification threshold: above this level its biological safety must be established.
Drug products follow similar, dose-banded thresholds for degradation products under ICH Q3B. Pharmacopoeias such as the IP, USP and EP also list specified impurities and limits in individual monographs.
How impurities are detected and measured
The workhorse technique is HPLC (high-performance liquid chromatography) with UV detection, used for "related substances" testing. Other techniques include:
- LC-MS and LC-MS/MS: for identifying unknown peaks and for trace-level impurities such as nitrosamines.
- GC and GC-MS: for volatile impurities and residual solvents.
- NMR: for confirming the structure of isolated impurities.
- ICP-MS: for elemental impurities.
We explain the analytical side in detail in How impurity standards are used in HPLC and LC-MS.
Why you need impurity reference standards
You cannot reliably control an impurity you cannot see or measure. An impurity reference standard, a well-characterised sample of the impurity itself, lets your lab:
- Confirm peak identity by matching retention time (and mass spectrum) with the standard.
- Quantify accurately, including determining the relative response factor (RRF).
- Develop and validate methods: specificity, LOD/LOQ, linearity and accuracy.
- Support stability studies by tracking known degradation products over time.
- Answer regulatory queries with documented, traceable data.
Examples from common Indian generics
Almost every API has a list of known impurities. A few examples of drug families where labs regularly need impurity standards:
- Metformin impurities, including nitrosamine risk assessment.
- Valsartan, Losartan and Telmisartan impurities (sartans).
- Atorvastatin and Amlodipine impurities.
- Sitagliptin, Dapagliflozin and Empagliflozin impurities (anti-diabetics).
- Ticagrelor impurities.
Key takeaways
- Pharmaceutical impurities are unavoidable, but they must be identified, measured and kept within limits.
- The main classes are organic impurities, inorganic impurities and residual solvents; mutagenic impurities need special control.
- Process-related impurities and degradation products need different control strategies.
- ICH Q3A/Q3B thresholds and pharmacopoeial monographs set when impurities must be reported, identified and qualified.
- Reliable, well-documented impurity reference standards are essential for every step of impurity control.
Looking for a specific impurity? Search our catalogue of 5,000+ impurity standards by name or CAS number, or send us your requirement.